Curriculum Vitaes

Toshiharu Nagatsu

  (永津 俊治)

Profile Information

Affiliation
Adviser of School of Medicine (Professor Emeritus(Fujita Health University, Nagoya University, Tokyo Insititute of Technology)), School of Medicine, Fujita Health University
Degree
(BLANK)

J-GLOBAL ID
200901072288633974
researchmap Member ID
1000102740

Research Interests

 2

Papers

 458
  • Toshiharu Nagatsu, Akira Nakashima, Hirohisa Watanabe, Shosuke Ito, Kazumasa Wakamatsu, Fabio A. Zucca, Luigi Zecca, Moussa Youdim, Maximilian Wulf, Peter Riederer, Johannes M. Dijkstra
    Journal of Neural Transmission, Mar 20, 2023  
    Abstract The dark pigment neuromelanin (NM) is abundant in cell bodies of dopamine (DA) neurons in the substantia nigra (SN) and norepinephrine (NE) neurons in the locus coeruleus (LC) in the human brain. During the progression of Parkinson’s disease (PD), together with the degeneration of the respective catecholamine (CA) neurons, the NM levels in the SN and LC markedly decrease. However, questions remain among others on how NM is associated with PD and how it is synthesized. The biosynthesis pathway of NM in the human brain has been controversial because the presence of tyrosinase in CA neurons in the SN and LC has been elusive. We propose the following NM synthesis pathway in these CA neurons: (1) Tyrosine is converted by tyrosine hydroxylase (TH) to L-3,4-dihydroxyphenylalanine (L-DOPA), which is converted by aromatic L-amino acid decarboxylase to DA, which in LC neurons is converted by dopamine β-hydroxylase to NE; (2) DA or NE is autoxidized to dopamine quinone (DAQ) or norepinephrine quinone (NEQ); and (3) DAQ or NEQ is converted to eumelanic NM (euNM) and pheomelanic NM (pheoNM) in the absence and presence of cysteine, respectively. This process involves proteins as cysteine source and iron. We also discuss whether the NM amounts per neuromelanin-positive (NM+) CA neuron are higher in PD brain, whether NM quantitatively correlates with neurodegeneration, and whether an active lifestyle may reduce NM formation.
  • Toshiharu Nagatsu, Akira Nakashima, Hirohisa Watanabe, Shosuke Ito, Kazumasa Wakamatsu
    International Journal of Molecular Sciences, 23(8) 4176-4176, Apr 10, 2022  
  • Johannes M Dijkstra, Toshiharu Nagatsu
    Journal of neural transmission (Vienna, Austria : 1996), Dec 10, 2021  
    Psychotherapies aim to relieve patients from mental distress by guiding them toward healthier attitudes and behaviors. Psychotherapies can differ substantially in concepts and approaches. In this review article, we compare the methods and science of three established psychotherapies: Morita Therapy (MT), which is a 100-year-old method established in Japan; Cognitive Behavioral Therapy (CBT), which-worldwide-has become the major psychotherapy; and Acceptance and Commitment Therapy (ACT), which is a relatively young psychotherapy that shares some characteristics with MT. The neuroscience of psychotherapy as a system is only beginning to be understood, but relatively solid scientific information is available about some of its important aspects such as learning, physical health, and social interactions. On average, psychotherapies work best if combined with pharmacotherapies. This synergy may rely on the drugs helping to "kickstart" the use of neural pathways (behaviors) to which a patient otherwise has poor access. Improved behavior, guided by psychotherapy, can then consolidate these pathways by their continued usage throughout a patient's life.
  • Kazuhisa Ikemoto, Chiho Sumi-Ichinose, Yui Suganuma, Taiki Kano, Noriko Ihira, Toshiharu Nagatsu, Kazunao Kondo
    The Journal of Biochemistry, Jun 28, 2021  
    <title>Abstract</title> Neopterin (NP), biopterin (BP) and monapterin (MP) exist in saliva. The physiological role of salivary NP as well as the pathophysiological role of increased NP in the immune-activated state has been unclear. Saliva is a characteristic specimen different from other body fluids. In this study, we analysed salivary NP and related pterin compounds, BP and MP and revealed some of its feature. High-performance liquid chromatography (HPLC) analysis of saliva and plasma obtained from 26 volunteers revealed that salivary NP existed mostly in its fully oxidized form. The results suggested that salivary NP as well as BP would mostly originate from the oral cavity, perhaps the salivary glands, and that salivary NP levels might not reflect those in the plasma. We also found that a gender difference existed in correlations between concentrations of salivary total concentrations of NP (tNP) and BP (tBP). HPLC analysis of saliva obtained from 5 volunteers revealed that the concentrations of salivary tNP as well as tBP fluctuated in an irregular fashion in various individuals. MP, a diastereomer of NP, might have come from oral cavity NP itself or its precursor. These results indicated that the nature of salivary NP might be different from that of NP in the blood or urine.
  • Akira Nakashima, Hisateru Yamaguchi, Mii Kondo, Takahiro Furumura, Yu Kodani, Yoko S Kaneko, Miho Kawata, Hiroshi Nagasaki, Toshiharu Nagatsu, Akira Ota
    Journal of neural transmission (Vienna, Austria : 1996), Aug 10, 2020  Peer-reviewed
    5'-Nucleotidase domain-containing protein 2 (NT5DC2) has been revealed by genome-wide association studies (GWAS) as a gene implicated in neuropsychiatric disorders related to the abnormality of dopamine (DA) activity in the brain. Based on its amino acid sequence, NT5DC2 is assumed to be a member of the family of haloacid dehalogenase-type phosphatases; although there is no information about its function and structural conformation. We recently reported that NT5DC2 binds to tyrosine hydroxylase (TH) and that the down-regulation of NT5DC2 tended to increase DA synthesis. In this study, we investigated whether NT5DC2 could regulate the catalytic activity of TH, which converts tyrosine to DOPA, because the phosphorylation level of TH, controlled by protein kinases and phosphatases, is well known to regulate its catalytic activity. The down-regulation of NT5DC2 by siRNA increased mainly DOPA synthesis by TH in PC12D cells, although this down-regulation tended to increase the conversion of DOPA to DA by aromatic L-amino acid decarboxylase. The increased DOPA synthesis should be attributed to the catalytic activity of TH controlled by its phosphorylation, because Western blot analysis revealed that the down-regulation of NT5DC2 tended to increase the level of TH phosphorylated at its Ser residues, but not that of the TH protein. Moreover, the induction of kinase activity by forskolin markedly potentiated the phosphorylation of TH at its Ser40 in PC12D cells having down-regulated NT5DC2. Immunocytochemical analysis of PC12D cells demonstrated that NT5DC2, TH protein, and TH phosphorylated at its Ser40 were predominantly localized in the cytoplasm and that the localization of NT5DC2 and TH proteins partially overlapped. Collectively, our results indicate that NT5DC2 could work to inhibit the DOPA synthesis by decreasing the phosphorylation of TH at its Ser40. We propose that NT5DC2 might decrease this phosphorylation of TH by promoting dephosphorylation or by inhibiting kinase activity.

Misc.

 354
  • Toshiharu Nagatsu, Ikuko Nagatsu
    JOURNAL OF NEURAL TRANSMISSION, 123(11) 1255-1278, Nov, 2016  
    Tyrosine hydroxylase (TH), which was discovered at the National Institutes of Health (NIH) in 1964, is a tetrahydrobiopterin (BH4)-requiring monooxygenase that catalyzes the first and rate-limiting step in the biosynthesis of catecholamines (CAs), such as dopamine, noradrenaline, and adrenaline. Since deficiencies of dopamine and noradrenaline in the brain stem, caused by neurodegeneration of dopamine and noradrenaline neurons, are mainly related to non-motor and motor symptoms of Parkinson's disease (PD), we have studied human CA-synthesizing enzymes [TH; BH4-related enzymes, especially GTP-cyclohydrolase I (GCH1); aromatic l-amino acid decarboxylase (AADC); dopamine beta-hydroxylase (DBH); and phenylethanolamine N-methyltransferase (PNMT)] and their genes in relation to PD in postmortem brains from PD patients, patients with CA-related genetic diseases, mice with genetically engineered CA neurons, and animal models of PD. We purified all human CA-synthesizing enzymes, produced their antibodies for immunohistochemistry and immunoassay, and cloned all human genes, especially the human TH gene and the human gene for GCH1, which synthesizes BH4 as a cofactor of TH. This review discusses the historical overview of TH, BH4-, and other CA-related enzymes and their genes in relation to the pathophysiology of PD, the development of drugs, such as l-DOPA, and future prospects for drug and gene therapy for PD, especially the potential of induced pluripotent stem (iPS) cells.
  • 金子葉子, 中島昭, 長崎弘, 小谷侑, 永津俊治, 太田明
    日本分子生物学会年会プログラム・要旨集(Web), 37th WEB ONLY 1P-0704, 2014  
  • Akira Nakashima, Yoko S. Kaneko, Keiji Mori, Hiroshi Nagasaki, Toshiharu Nagatsu, Akira Ota
    Catecholamine Research in the 21st Century: Abstracts and Graphical Abstracts, 10th International Catecholamine Symposium, 2012, 11-12, Dec 1, 2013  
  • Y. S. Kaneko, A. Nakashima, K. Mori, H. Nagasaki, Y. Kodani, I. Nagatsu, T. Nagatsu, A. Ota
    JOURNAL OF NEUROCHEMISTRY, 123 64-64, Oct, 2012  
  • A. Nakashima, Y. S. Kaneko, K. Mori, H. Nagasaki, T. Nagatsu, A. Ota
    JOURNAL OF NEUROCHEMISTRY, 123 117-117, Oct, 2012  
  • Akira Nakashima, Yoko Kaneko, Keiji Mori, Toshiharu Nagatsu, Akira Ota
    JOURNAL OF PHYSIOLOGICAL SCIENCES, 60 S111-S111, 2010  
  • Keiji Mori, Yoko S. Kaneko, Akira Nakashima, Toshiharu Nagatsu, Ikuko Nagatsu, Akira Ota
    NEUROSCIENCE RESEARCH, 68 E418-E418, 2010  
  • Toshiharu Nagatsu, Makoto Sawada
    PARKINSONISM & RELATED DISORDERS, 15 S3-S8, Jan, 2009  Peer-reviewed
    Dopamine (DA) supplementation therapy by L-dopa for Parkinson's disease (PD) was established around 1970. The dose of L-dopa can be reduced by the combined administration of inhibitors of peripheral L-amino acid decarboxylase (AADC), catechol O-methyltransferase (COMT). or monoamine oxidase B (MAO B). DA in the striatum may be produced from exogenously administered L-dopa by various AADC-containing cells. Such us serotonin neurons. The long-term administration of L-dopa in PD patients may produce L-dopa-induced dyskinesia (LID). which may be due to chronic overstimulation of supersensitive DA D1 receptors. L-dopa may be used in combination with various new strategies Such as gene therapy or transplantation in the future. (c) 2008 Elsevier Ltd. All rights reserved.
  • Yoko S. Kaneko, Akira Nakashima, Keiji Mori, Toshiharu Nagatsu, Ikuko Nagatsu, Akira Ota
    JOURNAL OF PHYSIOLOGICAL SCIENCES, 59 157-157, 2009  
  • Akira Nakashima, Yoko S. Kaneko, Keiji Mori, Toshiharu Nagatsu, Akira Ota
    JOURNAL OF PHYSIOLOGICAL SCIENCES, 59 475-475, 2009  
  • Hirohide Sawada, Hiromi Suzuki, Toshiharu Nagatsu, Makoto Sawada
    NEUROSCIENCE RESEARCH, 65 S118-S118, 2009  
  • Nakashima A, Hayashi N, Kaneko YS, Mori K, Sabban EL, Nagatsu T, Ota A
    J Neural Transm., 116(11) 1355-1362, 2009  
  • A. Nakashima, N. Hayashi, Y. S. Kaneko, K. Mori, E. L. Sabban, T. Nagatsu, A. Ota
    JOURNAL OF NEURAL TRANSMISSION, 115(10) 1471-1471, Oct, 2008  
  • SAWADA Makoto, SAWADA Hirohide, NAGATSU Toshiharu
    Neurodegener Dis, 5(3-4) 254-256, Mar, 2008  Peer-reviewed
  • Kouji Yamada, Hirohide Sawada, Kazuhiro Nishii, Naohiro Ichino, Takehiko Hida, Shizuko Nagao, Hisahide Takahashi, Hisahide Takahashi, Hiroshi Ishiguro, Toshiharu Nagatsu
    Biogenic Amines, 21 183-194, Dec 1, 2007  
    Several reports on different in vitro and in vivo models have revealed neuroprotective effects afforded by nicotine treatment. Nicotine is a cognitive enhancer that acts by increasing vigilance and improving learning and memory. We previously reported that nicotine withdrawal up-regulated transcription of some immediately early genes (IEGs), apoptosis-related genes, and signal transduction-related genes in cultures of pheochromocytoma PC12 cells, which are of neuronal lineage (Ichino et al., 1999; Ichino et al., 2002; Yamada et al., 2005). Especially, nicotine withdrawal increased the levels of Bag-1, Rab2, Hsp70, and Raf1 proteins in the cerebral cortex, hippocampus, and striatum in vivo in mice. Egr-1 and Nur77 protein levels were dramatically increased by nicotine withdrawal. (Yamada et al., 2006). Also, there is a study that analyzed the expression of mRNAs by in situ hybridization using a rat genome array after acute intermittent nicotine treatment and found that some mRNA levels of them (Nr4a1, Egr-1 and Egr-2) are significantly up-regulated in the rat cerebral cortex and hippocampal regions (Belluardo et al., 2005). In the present study, we aimed at further elucidating the effects of nicotine withdrawal on the expression of the upstream proteins of IEGs in the brain of mice after chronic administration of nicotine. We observed significant increases in the protein levels of Egr-1 and Nur77 in the specific regions and in specific cells in the mouse brain by Western blot analysis and by immunohistochemistry. The present results suggest that such changes may also occur in the brain of smokers during abstaining from smoking and may be related to some of their symptoms of nicotine withdrawal. © Society of Integrated Sciences.
  • Hiroaki Sakane, Chiho Sumi-Ichinose, Masayo Kojima, Yoshinori Aso, Shin-ichi Muramatsu, Imaharu Nakano, Keiya Ozawa, Takahide Nomura, Ikuko Nagatsu, Toshiharu Nagatsu, Daniel Metzger, Pierre Chambon, Hiroshi Ichinose
    NEUROSCIENCE RESEARCH, 58 S138-S138, 2007  
  • Toshiharu Nagatsu
    PROCEEDINGS OF THE JAPAN ACADEMY SERIES B-PHYSICAL AND BIOLOGICAL SCIENCES, 82(10) 388-415, Dec, 2006  
    Catecholamines [dopamine, noradrenaline (norepinephrine), and adrenaline (epinephrine); CAs] are neurotransmitters in the central and peripheral nervous systems as well as hormones in the endocrine system. CAs in the brain play a central role in versatile functions as slow-acting neurotransmitters functioning in synaptic neurotransmission, modulating the effects of fast-acting neurotransmitters such as glutamate and gamma-aminobutyric acid (GABA). In this review, I focus on recent advances in the biochemistry and molecular biology of the CA system in humans in health and disease, especially in neuropsychiatric diseases such as Parkinson's disease (PD), in relation to the biosynthesis of CAs regulated by a pteridine-dependent monooxygenase, tyrosine 3-monooxygenase (tyrosine hydroxylase, TH) and its pteridine cofactor, tetrahydrobiopterin (BH4).
  • Toshiharu Nagatsu
    PROCEEDINGS OF THE JAPAN ACADEMY SERIES A-MATHEMATICAL SCIENCES, 82(10) 388-415, Dec, 2006  
    Catecholamines [dopamine, noradrenaline (norepinephrine), and adrenaline (epinephrine); CAs] are neurotransmitters in the central and peripheral nervous systems as well as hormones in the endocrine system. CAs in the brain play a central role in versatile functions as slow-acting neurotransmitters functioning in synaptic neurotransmission, modulating the effects of fast-acting neurotransmitters such as glutamate and gamma-aminobutyric acid (GABA). In this review, I focus on recent advances in the biochemistry and molecular biology of the CA system in humans in health and disease, especially in neuropsychiatric diseases such as Parkinson's disease (PD), in relation to the biosynthesis of CAs regulated by a pteridine-dependent monooxygenase, tyrosine 3-monooxygenase (tyrosine hydroxylase, TH) and its pteridine cofactor, tetrahydrobiopterin (BH4).
  • 山田晃司, 沢田浩秀, 西井一宏, 市野直浩, 肥田岳彦, 石黒啓司, 永津俊治
    解剖学雑誌, 81(Supplement) 174-174, Mar, 2006  
  • T. Nagatsu, M. Sawada
    JOURNAL OF NEURAL TRANSMISSION-SUPPLEMENT, (71) 53-65, 2006  
    Monoamine oxidases A and B (MAO A and MAO B) are the major enzymes that catalyze the oxidative deamination of monoamine neurotaransmitters such as dopamine (DA), noradrenaline, and serotonin in the central and peripheral nervous systems. MAO B is mainly localized in glial cells. MAO B also oxidizes the xenobiotic 1-methyl-4-phenyl-1.2.3,6-tetrahydropyridine (MPP+) to a parkinsonism-producing neurotoxin, 1-methyl-4-phenyl-pyridinium (MPP+). MAO B may be closely related to the pathogenesis of Parkinson's disease (PD), in which neuromelanin-containing DA neurons in the substantia nigra projecting to the striatum in the brain selectively degenerate. MAO B degrades the neurotransmitter DA that is deficient in the nigro-striatal region in PD, and forms H,02 and toxic aldehyde metabolites of DA. H2O2 produces highly toxic reactive oxygen species (ROS) by Fenton reaction that is catalyzed by iron and neuromelanin. MAO B inhibitors such as L-(-)-deprenyl (selegiline) and rasagiline are effective for the treatment of PD. Concerning the mechanism of the clinical efficacy of MAO B inhibitors in PD, the inhibition of DA degradation (a symptomatic effect) and also the prevention of the formation of neurotoxic DA metabolites, i.e., ROS and dopamine derived aldehydes have been speculated. As;mother mechanism of clinical efficacy, MAO B inhibitors such as selegiline are speculated to have neuroprotective effects to prevent progress of PD. The possible mechanism of neuroprotection of MAO B inhibitors may be related not only to MAO B inhibition but also to induction and activation of multiple factors for anti-oxidative stress and anti-apoptosis: i.e., catalase, superoxide dismutase 1 and 2, thioredoxin, Bcl-2, the cellular poly(ADP-ribosyl)ation, and binding to glyceraldehydes-3-phosphate dehydrogenase (GAPDH). Furthermore, it should be noted that selegiline increases production of neurotrophins such as nerve growth factor (NGF), brain-derivec neurotrophic factor (BDNF), and glial cell line-derived neurotrphic factor (GDNF), possibly from glial cells, to protect neurons from inflammatory process.
  • Hirohide Sawada, Ryohei Hishida, Yoko Hirata, Kenji Ono, Hiromi Suzuki, Shin-ichi Muramatsu, Imaharu Nakano, Kunihiro Tsuchida, Toshiharu Nagatsu, Makoto Sawada
    NEUROSCIENCE RESEARCH, 55 S201-S201, 2006  
  • 山田晃司, 沢田浩秀, 西井一宏, 市野直浩, 肥田岳彦, 石黒啓司, 永津俊治
    日本分子生物学会年会講演要旨集, 28th 658, Nov 25, 2005  
  • 沢田浩秀, 山田晃司, 西井一宏, 永津俊治, 石黒啓司
    日本組織細胞化学会総会・学術集会講演プログラム・予稿集, 46th 52-52, Oct, 2005  
  • 山田 晃司, 石黒 啓司, 市野 直浩, 西井 一宏, 澤田 浩秀, 永津 俊治, 肥田 岳彦
    解剖学雑誌, 80(Suppl.) 248-248, Mar, 2005  
  • T Nagatsu, M Sawada
    CURRENT PHARMACEUTICAL DESIGN, 11(8) 999-1016, 2005  
    Parkinson's disease (PD) is a movement disorder caused by degeneration of the nigrostriatal dopamine (DA) neurons in the substantia nigra pars compacta and the resultant deficiency in the neurotransmitter DA at the nerve terminals in the striatum. We and other investigators found increased levels of pro-inflammatory cytokines Such as tumor necrosis factor (TNF)-alpha, interleukin (IL)1lbeta, and IL-6, and decreased levels of neurotrophins such as brain-derived neurotrophic factor (BDNF) in the nigrostriatal region of postmortem brains and/or in the ventricular or lumbar cerebrospinal fluid (CSF) from patients with sporadic PD, and in animal models, such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)- and 6-hydroxydopamine (6-OHDA)-induced PD. These changes in cytokine and neurotrophin levels may be initiated by activated microglia, which may then promote apoptotic cell death and subsequent phagocytosis of DA neurons. Cytokines as pleiotropic factors, promote signals that either lead to cell death or exert neuroprotective effects. The discovery of toxic changes in trophic microglia by M. Sawada and co-workers is important to this point. Ultimately, microglial cells may regulate Cellular changes that cause either harm or benefit by producing cytokines or neurotrophins depending upon the primary cause and the circumstances during the inflammatory process of PD.
  • TAKATSUNA Hiroshi, MORITA Shigeru, NAGATSU Toshiharu, SAWADA Makoto, UMEZAWA Kazuo
    Biomedecine & Pharmacotherapy, 59 318-322, 2005  Peer-reviewed
    Activation of microglia has been implicated in various neurodegenerative disorders, and thus the inhibition of microglial activity may suppress these disorders. Earlier we designed and synthesized an NF-kappaB inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ) that showed anti-inflammatory and anti-tumor activities in vivo. In the present research, we studied whether DHMEQ would inhibit the activation of mouse microglial cells. DHMEQ inhibited lipopolysaccharide (LPS)-induced activation of NF-kappaB in an electrophoresis mobility shift assay. It also inhibited LPS-induced secretions of TNF-alpha and IL-6 from mouse microglial cell line 6-1 cells.
  • Nakashima A, Kaneko YS, Mori K, Nagatsu T, Ota A
    Biogenic Amines., 19(4-6) 279-288, 2005  
  • Kaneko YS, Mori K, Nakashima A, Nagatsu I, Nagatsu T, Ota A
    Biogenic Amines., 19(4-6) 289-297, 2005  
  • 山田晃司, 市野直浩, 西井一宏, 沢田浩秀, 肥田岳彦, 石黒啓司, 永津俊治
    日本分子生物学会年会プログラム・講演要旨集, 27th 571, Nov 25, 2004  
  • H Takubo, T Harada, T Hashimoto, Y Inaba, Kanazawa, I, S Kuno, Y Mizuno, E Mizuta, M Murata, T Nagatsu, S Nakamura, N Yanagisawa, H Narabayashi
    PARKINSONISM & RELATED DISORDERS, 9 S31-S41, Apr, 2003  
    We report the results of a collaborative study on malignant syndrome (MS) that developed in patients being treated with levodopa and other anti-parkinsonian drugs. We analyzed clinical features, laboratory findings, precipitating events, and risk factors for poor outcome. The study was conducted in five centers in Japan. Patients who developed MS between January 1991 and December 1997 were included. The enrollment criteria used were the same as those for neuroleptic MS proposed by Levenson et al. (1985). A total of 99 episodes were encountered in 93 patients (72 with Parkinson's disease and 21 with secondary parkinsonism); one patient had four recurrences of MS and three patients had two recurrences. High fever was the most frequent clinical manifestation of MS followed by worsening of parkinsonism, and then altered levels of consciousness. Serum creatine kinase was abnormally elevated in all the patients studied. Life-threatening complications were rhabdomyolysis, disseminated intravascular coagulation, and acute renal failure. The most frequent precipitating event was discontinuation or dose reduction of anti-parkinsoian drugs, particularly levodopa. No drug was the exception in the precipitation of MS. Intercurrent infection was the next most common precipitating event. MS developed without drug withdrawal or infection in some patients. In five patients, severe 'wearing off' phenomenon was the only event preceding the onset of MS. Hot weather and dehydration appeared to be the cause in three patients. Among the total of 99 episodes, patients recovered to the pre-MS state following 68 episodes (68.7%); in the remaining 31.3%, patients failed to recover to their previous state. Older age, higher Hoehn and Yahr stage during the symptomatic phase of MS, higher akinesia score, and the absence of wearing off phenomenon prior to developing MS were associated with poor outcome. The most frequently used treatments of MS were intravenous fluid, levodopa, dantrolene sodium, and intragastric bromocriptine. Early introduction of treatment is important. Any elevation of body temperature during the course of anti-parkinsonian drug treatment should be considered as MS until proved otherwise. (C) 2003 Elsevier Science Ltd. All rights reserved.
  • 沢田浩秀, 西井一宏, 山田晃司, 後藤順, 金沢一郎, 永津俊治, 石黒啓司
    日本神経科学大会プログラム・抄録集, 25th 174, Jul 7, 2002  
  • T Yamakuni, T Yamamoto, H Yamamoto, SY Song, T Nagatsu, M Yokoyama, A Nakano, R Suzuki, C Kato, M Kobayashi, Y Ishida, K Kobayashi, Y Ohizumi
    JAPANESE JOURNAL OF PHARMACOLOGY, 88 226P-226P, 2002  
  • R Kuroda, C Sumi-Ichinose, F Urano, T Ohye, H Shiraishi, M Tazawa, T Nagatsu, H Ichinose, Y Hagino, T Nomura
    JAPANESE JOURNAL OF PHARMACOLOGY, 88 189P-189P, 2002  
  • 金子鋭, 疋田貴俊, 渡辺大, 一瀬宏, 永津俊治, KREITMAN R J, PASTAN I, 中西重忠
    臨床神経学, 41(11) 860, Nov 1, 2001  
  • 沢田浩秀, 西井一宏, 山田晃司, 後藤順, 金沢一郎, 永津俊治, 石黒啓司
    日本神経科学大会プログラム・抄録集, 24th 366, Sep 26, 2001  
  • 沢田浩秀, 西井一宏, 山田晃司, 後藤順, 金沢一郎, 永津俊治, 石黒啓司
    神経化学, 40(2/3) 422-422, Sep 1, 2001  
  • 石黒啓司, 沢田浩秀, 西井一宏, 山田晃司, 後藤順, 金沢一郎, 永津俊治
    生化学, 73(8) 1072-1072, Aug 25, 2001  
  • 沢田浩秀, 西井一宏, 山田晃司, 市野直浩, 沢田誠, 石黒啓司, 黒沢良和, 永津俊治
    生化学, 73(5) 402-402, May 25, 2001  
  • M Ota, A Nakashima, K Ikemoto, S Nojima, M Tanaka, M Okuda, H Koga, K Mori, YS Kaneko, K Fujiwara, H Yamamoto, T Nagatsu, A Ota
    MOLECULAR PSYCHIATRY, 6(3) 315-319, May, 2001  
    Tyrosine hydroxylase (TH) is the rate-limiting enzyme in dopamine (DA) biosynthesis.(1,2) Exon 3 of the human TH gene encodes the sequence from Ser31 to Glu104 of type 1 enzyme,(3,4) which contains the critical parts for regulation of the catalytic activity. The amino acid residues Gly36-Arg37-Arg38 were identified as a key sequence for DA to exert its inhibitory effect on catalytic activity.(5-7) Therefore, we screened the nucleotide sequences of exon 3 from 201 Japanese patients with schizophrenia to explain the elevation in the synaptic or presynaptic DA concentrations in the schizophrenic brain,(8-11) based on the hypothesis that any mutation changing the amino acid sequence Gly36-Arg37-Arg38 would result in the elevation of DA synthesis, due to a reduced inhibitory effect of DA on the catalytic activity.(5-7) However, no mutated sequences of exon 3 and both exon-intron boundaries were detected in any of the patients examined. Polymorphisms generating Val81 and Met81 were compared of the distributions of genotype and allele between the patients and 175 Japanese healthy controls, which did not suggest an association between the polymorphism and schizophrenia. These results indicate that exon 3 of the human TH gene lacks association with schizophrenia in Japanese patients.
  • 金子鋭, 岡田隆之, 田丸佳子, 疋田貴俊, 渡辺大, 一瀬宏, 永津俊治, KREITMAN R J, PASTAN I
    大阪神経筋難病研究会特定疾患調査研究結果報告書, 2000 25-33, Mar, 2001  
  • M Mogi, A Togari, T Kondo, Y Mizuno, O Kogure, S Kuno, H Ichinose, T Nagatsu
    NEUROSCIENCE LETTERS, 300(3) 179-181, Mar, 2001  
    Glial cell line-derived neurotrophic factor (GDNF) was measured for the first time in the brain (substantia nigra, caudate nucleus, putamen, cerebellum, and frontal cortex) from control and parkinsonian patients by highly sensitive sandwich enzyme-linked immunosorbent assay. In both groups, the levels of GDNF in the various brain regions were lower (pg/mg protein) than those of brain-derived growth factor (ng/mg order), and were significantly higher in the nigro-striatal dopaminergic regions (substantia nigra, caudate nucleus, putamen) than in the cerebellum and frontal cortex (P &lt; 0.05). However, the content of GDNF in the dopaminergic regions showed no significant difference between parkinsonian and control patients. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.
  • CP Zabetian, GM Anderson, SG Buxbaum, RC Elston, H Ichinose, T Nagatsu, KS Kim, CH Kim, RT Malison, J Gelernter, JF Cubells
    AMERICAN JOURNAL OF HUMAN GENETICS, 68(2) 515-522, Feb, 2001  
    Dopamine-beta -hydroxylase (D betaH) catalyzes the conversion of dopamine to norepinephrine and is released from sympathetic neurons into the circulation. Plasma-D betaH activity varies widely between individuals, and a subgroup of the population has very low activity levels. Mounting evidence suggests that the DBH structural gene is itself the major quantitative-trait locus (QTL) for plasma-D betaH activity, and a single unidentified polymorphism may account for a majority of the variation in activity levels. Through use of both sequencing-based mutational analysis of extreme phenotypes and genotype/phenotype correlations in samples from African American, European American (EA), and Japanese populations, we have identified a novel polymorphism (-1021C--&gt;T), in the 5' flanking region of the DBH gene, that accounts for 35%-52% of the variation in plasma-DbH activity in these populations. In EAs, homozygosity at the T allele predicted the very low D betaH-activity trait, and activity values in heterozygotes formed an intermediate distribution, indicating codominant inheritance. Our findings demonstrate that -1021C--&gt;T is a major genetic marker for plasma-D betaH activity and provide new tools for investigation of the role of both DbH and the DBH gene in human disease.
  • Ishiguro H, Sawada H, Nishii K, Yamada K, Nagatsu T
    Brain and Nerve, 53(9) 829-837, 2001  
  • T Sugimoto, K Ikemoto, S Murata, M Tazawa, T Nomura, Y Hagino, H Ichinose, T Nagatsu
    HELVETICA CHIMICA ACTA, 84(4) 918-927, 2001  
    The structure of the native pteridine in Tetrahymena pyriformis was determined as (6R)-5,6,7,8-tetrahydro-D-monapterin (=(6R)-2-amino-5.6.7.8-tetrahydro-6-[(1R,2R)-1,2,3-trihydroxypropyl)]pteridin-4(3II)-one:4). First, the configuration of the 1.2.3-trihydroxypropyl side chain was confirmed as D-threo by the fluorescence-detected circular dichroism (FDCD) spectrum of its aromatic pterin derivative 2 obtained by 1(2) oxidation (fig. 1.). The configuration at the 6-position of 4 was determined as (R) by comparison of its hexaacetyl derivative 6 with authentic (6R)- and (6S)-hexaacetyl-5,6,7,8-tetrahydro-D-monapterins 6 and 7, respectvely, in the HPLC, LC/MS and LC-MS.MS (figs. 3-6), (6R)-5,6,7,8-Tetrahydro-D-monapterin (4) is a newly discovered natural tetrahydropterin.
  • T Sugimoto, K Ikemoto, S Murata, M Tazawa, T Nomura, Y Hagino, H Ichinose, T Nagatsu, A Wada
    HETEROCYCLES, 54(1) 283-290, Jan, 2001  
    The major pterin from Escherichia coli was determined as L-monapterin, by applying fluorescence detected circular dichroism (FDCD). FDCD was highly sensitive and specific to fluorescent chiral pterin, and allowed structure determination even in the presence of non-fluorescent contaminants.
  • ICHINOSE Hiroshi
    40(12) 1284-1286, Dec 1, 2000  
  • H Ishiguro, K Yamada, H Sawada, K Nishii, N Ichino, M Sawada, Y Kurosawa, N Matsushita, K Kobayashi, J Goto, Kanazawa, I, T Nagatsu
    AMERICAN JOURNAL OF HUMAN GENETICS, 67(4) 348-348, Oct, 2000  
  • CP Zabetian, GM Anderson, J Gelernter, H Ichinose, T Nagatsu, RT Malison, JF Cubells
    AMERICAN JOURNAL OF HUMAN GENETICS, 67(4) 179-179, Oct, 2000  

Books and Other Publications

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Research Projects

 44